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1.
Respir Res ; 24(1): 280, 2023 Nov 14.
Article in English | MEDLINE | ID: mdl-37964270

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic fatal disease with limited therapeutic options. The infiltration of monocytes and fibroblasts into the injured lungs is implicated in IPF. Enolase-1 (ENO1) is a cytosolic glycolytic enzyme which could translocate onto the cell surface and act as a plasminogen receptor to facilitate cell migration via plasmin activation. Our proprietary ENO1 antibody, HL217, was screened for its specific binding to ENO1 and significant inhibition of cell migration and plasmin activation (patent: US9382331B2). METHODS: In this study, effects of HL217 were evaluated in vivo and in vitro for treating lung fibrosis. RESULTS: Elevated ENO1 expression was found in fibrotic lungs in human and in bleomycin-treated mice. In the mouse model, HL217 reduced bleomycin-induced lung fibrosis, inflammation, body weight loss, lung weight gain, TGF-ß upregulation in bronchial alveolar lavage fluid (BALF), and collagen deposition in lung. Moreover, HL217 reduced the migration of peripheral blood mononuclear cells (PBMC) and the recruitment of myeloid cells into the lungs. In vitro, HL217 significantly reduced cell-associated plasmin activation and cytokines secretion from primary human PBMC and endothelial cells. In primary human lung fibroblasts, HL217 also reduced cell migration and collagen secretion. CONCLUSIONS: These findings suggest multi-faceted roles of cell surface ENO1 and a potential therapeutic approach for pulmonary fibrosis.


Subject(s)
Idiopathic Pulmonary Fibrosis , Pneumonia , Mice , Humans , Animals , Leukocytes, Mononuclear/metabolism , Antibodies, Monoclonal/therapeutic use , Endothelial Cells/metabolism , Fibrinolysin/metabolism , Fibrinolysin/pharmacology , Fibrinolysin/therapeutic use , Lung/metabolism , Fibrosis , Idiopathic Pulmonary Fibrosis/chemically induced , Idiopathic Pulmonary Fibrosis/drug therapy , Idiopathic Pulmonary Fibrosis/metabolism , Pneumonia/metabolism , Collagen/metabolism , Bleomycin/toxicity , Fibroblasts/metabolism , Phosphopyruvate Hydratase/metabolism , Phosphopyruvate Hydratase/pharmacology , Phosphopyruvate Hydratase/therapeutic use , Mice, Inbred C57BL
2.
Oncol Rep ; 50(5)2023 Nov.
Article in English | MEDLINE | ID: mdl-37800625

ABSTRACT

The involvement of enolase­1 (ENO1), intracellularly or extracellularly, has been implicated in cancer development. Moreover, anticancer activities of an ENO1­targeting antibody has demonstrated the pathological roles of extracellular ENO1 (surface or secreted forms). However, although ENO1 was first identified as a glycolytic enzyme in the cytosol, to the best of our knowledge, extracellular ENO1 has not been implicated in glycolysis thus far. In the present study, the effects of extracellular ENO1 on glycolysis and other related pro­cancer activities were investigated in multiple myeloma (MM) cells in vitro and in vivo. Knockdown of ENO1 expression reduced lactate production, cell viability, cell migration and surface ENO1 expression in MM cells. Notably, addition of extracellular ENO1 protein in cancer cell culture enhanced glycolytic activity, hypoxia­inducible factor 1­α (HIF­1α) expression, glycolysis­related gene (GRG) expression and pro­cancer activities, such as cell migration, cell viability and tumor­promoting cytokine secretion. Consistently, these extracellular ENO1­induced cellular effects were inhibited by an ENO1­specific monoclonal antibody (mAb). In addition, extracellular ENO1­mediated glycolysis, GRG expression and pro­cancer activities were also reduced by HIF­1α silencing. Lastly, administration of an ENO1 mAb reduced tumor growth and serum lactate levels in an MM xenograft model. These results suggested that extracellular ENO1 (surface or secreted forms) enhanced a HIF­1α­mediated glycolytic pathway, in addition to its already identified roles. Therefore, the results of the present study highlighted the therapeutic potential of ENO1­specific antibodies in treating MM, possibly via glycolysis inhibition, and warrant further studies in other types of cancer.


Subject(s)
Glycolysis , Multiple Myeloma , Humans , Antibodies, Monoclonal/metabolism , Biomarkers, Tumor/metabolism , Cell Line, Tumor , Cell Proliferation/genetics , DNA-Binding Proteins/metabolism , Glycolysis/genetics , Lactates , Multiple Myeloma/genetics , Phosphopyruvate Hydratase/genetics , Phosphopyruvate Hydratase/metabolism , Tumor Suppressor Proteins/metabolism , Animals , Mice , Xenograft Model Antitumor Assays
3.
Cytotherapy ; 25(7): 683-698, 2023 07.
Article in English | MEDLINE | ID: mdl-37097265

ABSTRACT

The 5th Asia Partnership Conference of Regenerative Medicine (APACRM) was held online on April 7, 2022 to promote regulatory harmonization of regenerative medicine products throughout Asia. The recognition of domestic regulatory guidelines within each country and region and the underpinning rationales are important initial steps toward the harmonization of regulations. The 5th APACRM featured open dialog regarding non-clinical, quality and environmental impact assessment settings for cell and gene therapy products through presentations from the industry and panel discussions with regulatory agencies. The latest updates on regenerative medicine fields in each country and region were also introduced. This paper summarizes the proceedings of the 5th APACRM for public dissemination to foster future discussion.


Subject(s)
Environment , Regenerative Medicine , Asia , Genetic Therapy/adverse effects
4.
Mol Cancer Ther ; 21(8): 1337-1347, 2022 08 02.
Article in English | MEDLINE | ID: mdl-35700013

ABSTRACT

Prostate cancer is one of the most common causes of cancer death in men worldwide, and the treatment options are limited for patients with advanced stages of prostate cancer. Upon oncogenic or inflammatory stimulation, tumor cells or immune cells express cell surface enolase-1 (ENO1) as plasminogen receptor to facilitate their migration via plasmin activation. Little is known about the roles of ENO1 in prostate cancer, especially in the tumor microenvironment (TME). We hypothesized that targeting surface ENO1 with specific mAbs would exert multifactorial therapeutic potentials against prostate cancer. In vivo, we showed ENO1 mAb (HuL227) reduced the growth of subcutaneous PC-3 xenograft, monocytes recruitment, and intratumoral angiogenesis. In a PC-3 intratibial implantation model, HuL227 reduced tumor growth and osteoclast activation in the bone. To investigate the antitumor mechanism of ENO1 mAb, we found that blocking surface ENO1 significantly reduced VEGF-A-induced tube formation of endothelial cells in vitro. Furthermore, HuL227 inhibited inflammation-enhanced osteoclasts activity and the secretion of invasion-related cytokines CCL2 and TGFß from osteoclasts. In addition, inflammation-induced migration and chemotaxis of androgen-independent prostate cancer cells were dose-dependently inhibited by HuL227. In summary, we showed that, ENO1 mAb targets multiple TME niches involved in prostate cancer progression and bone metastasis via a plasmin-related mechanism, which may provide a novel immunotherapy approach for men with advanced prostate cancer.


Subject(s)
Prostatic Neoplasms , Tumor Microenvironment , Animals , Cell Line, Tumor , Endothelial Cells/metabolism , Fibrinolysin , Humans , Inflammation , Male , PC-3 Cells , Phosphopyruvate Hydratase/metabolism , Prostatic Neoplasms/pathology
5.
J Med Chem ; 64(3): 1435-1453, 2021 02 11.
Article in English | MEDLINE | ID: mdl-33492141

ABSTRACT

In this paper, we present a copper(I)-catalyzed nitrile-addition/N-arylation ring-closure cascade for the synthesis of 5,11-dihydro-6H-indolo[3,2-c]quinolin-6-ones from 2-(2-bromophenyl)-N-(2-cyanophenyl)acetamides. Using CuBr and t-BuONa in dimethylformamide (DMF) as the optimal reaction conditions, the cascade reaction gave the target products, in high yields, with a good substrate scope. Application of the cascade reaction was demonstrated on the concise total syntheses of alkaloid isocryptolepine. Further optimization of the products from the cascade reaction led to 3-chloro-5,12-bis[2-(dimethylamino)ethyl]-5,12-dihydro-6H-[1,3]dioxolo[4',5':5,6]indolo[3,2-c]quinolin-6-one (2k), which exhibited the characteristic DNA topoisomerase-I inhibitory mechanism of action with potent in vitro anticancer activity. Compound 2k actively inhibited ARC-111- and SN-38-resistant HCT-116 cells and showed in vivo activity in mice bearing human HCT-116 and SJCRH30 xenografts. The interaction of 2k with the Top-DNA cleavable complex was revealed by docking simulations to guide the future optimization of 5,11-dihydro-6H-indolo[3,2-c]quinolin-6-ones as topoisomerase-I inhibitors.


Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Copper/chemistry , Nitriles/chemistry , Quinolones/chemical synthesis , Quinolones/pharmacology , Topoisomerase I Inhibitors/chemical synthesis , Topoisomerase I Inhibitors/pharmacology , Animals , Catalysis , DNA Topoisomerases, Type I/chemistry , Drug Design , Drug Screening Assays, Antitumor , Female , Humans , Male , Mice , Mice, Nude , Models, Molecular , Molecular Docking Simulation , Quinolones/pharmacokinetics , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship , Topoisomerase I Inhibitors/pharmacokinetics , Xenograft Model Antitumor Assays
6.
Cells ; 10(1)2020 12 30.
Article in English | MEDLINE | ID: mdl-33396864

ABSTRACT

In natural infection, hepatitis B virus (HBV) core protein (HBc) accumulates frequent mutations. The most frequent HBc variant in chronic hepatitis B patients is mutant 97L, changing from an isoleucine or phenylalanine to a leucine (L) at HBc amino acid 97. One dogma in the HBV research field is that wild type HBV secretes predominantly virions containing mature double-stranded DNA genomes. Immature genomes, containing single-stranded RNA or DNA, do not get efficiently secreted until reaching genome maturity. Interestingly, HBc variant 97L does not follow this dogma in virion secretion. Instead, it exhibits an immature secretion phenotype, which preferentially secretes virions containing immature genomes. Other aberrant behaviors in virion secretion were also observed in different naturally occurring HBc variants. A hydrophobic pocket around amino acid 97 was identified by bioinformatics, genetic analysis, and cryo-EM. We postulated that this hydrophobic pocket could mediate the transduction of the genome maturation signal for envelopment from the capsid interior to its surface. Virion morphogenesis must involve interactions between HBc, envelope proteins (HBsAg) and host factors, such as components of ESCRT (endosomal sorting complex required for transport). Immature secretion can be offset by compensatory mutations, occurring at other positions in HBc or HBsAg. Recently, we demonstrated in mice that the persistence of intrahepatic HBV DNA is related to virion secretion regulated by HBV genome maturity. HBV virion secretion could be an antiviral drug target.


Subject(s)
Hepatitis B Core Antigens/genetics , Hepatitis B Surface Antigens/genetics , Hepatitis B virus , Hepatitis B, Chronic/virology , Virion/metabolism , Animals , Hepatitis B virus/genetics , Hepatitis B virus/physiology , Humans , Mice , Mutation , Virus Assembly
7.
In Vivo ; 29(4): 445-52, 2015.
Article in English | MEDLINE | ID: mdl-26130789

ABSTRACT

BACKGROUND/AIM: Interferon-α (IFN-α) is produced to act locally and transiently with a relatively short circulation half-life in vivo. Hybridization of IFN-α with human immunoglobulin Fc, renamed as IFN-α-Fc, may overcome this limitation. In the present study, (131)I-IFN-α-Fc and (131)I-IFN-α were compared in the aspects of stability, pharmacokinetics, tissue distribution and molecular imaging quality in an animal model. MATERIALS AND METHODS: Both IFN-α-Fc and IFN-α were labelled with (131)I. Biodistributions and pharmacokinetics of both labelled proteins in Sprague-Dawley rats were assayed. Micro-single-photon emission computed tomography/computed tomography was used to non-invasively monitor the longitudinal distribution of both proteins. RESULTS: (131)I-IFN-α-Fc was shown to have higher stability than (131)I-IFN-α in whole blood, plasma, kidney, liver and stomach from the biodistribution study. The area under curve analyzed from plasma in the phomacokinetics study was 10-fold higher for (131)I-IFN-α-Fc than for (131)I-IFN-α. At 0-1 h post tail-vein injection, both labelled proteins are mainly accumulated in the kidneys and liver. Notably, (131)I-IFN-α-Fc is degraded more slowly than (131)I-IFN-α. CONCLUSION: We demonstrated that (131)I-IFN-α-Fc has longer blood circulation time and better biostability than (131)I-IFN-α, suggesting the potential application of the immunoglobulin Fc-conjugated cytokine for long-term treatment of diseases.


Subject(s)
Immunoglobulin Fc Fragments/metabolism , Interferon-alpha/metabolism , Iodine Radioisotopes , Molecular Imaging/methods , Recombinant Fusion Proteins/metabolism , Animals , Interferon-alpha/pharmacokinetics , Male , Rats , Recombinant Fusion Proteins/pharmacokinetics , Tissue Distribution , Tomography, Emission-Computed, Single-Photon , X-Ray Microtomography
8.
Eur J Med Chem ; 45(12): 6068-76, 2010 Dec.
Article in English | MEDLINE | ID: mdl-21044810

ABSTRACT

A series of 3-O-acylated (-)-epigallocatechins were synthesized and their inhibition of steroid 5α-reductase was studied. They were prepared from the reaction of EGCG with tert-butyldimethylsilyl chloride followed by reductive cleavage of the ester bond. The resultant (-)-epigallocatechins penta-O-tert-butyldimethylsilyl ether was esterified with different fatty acids then desilylated to provide the corresponding products. The activity of 3-O-acylated (-)-epigallocatechins increased with the increasing carbon numbers of the fatty acid moiety, reaching maximum for 16 carbon atoms (compound 4h) with an IC50 of 0.53 µM, which was ∼12-fold more potent than EGCG (IC50=6.29 µM). Introduction of monounsaturated fatty acid provided the most potent compound 6 (IC50=0.48 µM), which showed moderate anti-tumor activity in vivo.


Subject(s)
3-Oxo-5-alpha-Steroid 4-Dehydrogenase/metabolism , 5-alpha Reductase Inhibitors/pharmacology , Antineoplastic Agents/pharmacology , Catechin/analogs & derivatives , 5-alpha Reductase Inhibitors/chemical synthesis , 5-alpha Reductase Inhibitors/chemistry , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Catechin/chemical synthesis , Catechin/chemistry , Catechin/pharmacology , Cell Line, Tumor , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Male , Mice , Mice, SCID , Models, Molecular , Molecular Structure , Stereoisomerism , Structure-Activity Relationship , Xenograft Model Antitumor Assays
9.
J Med Chem ; 53(16): 5929-41, 2010 Aug 26.
Article in English | MEDLINE | ID: mdl-20681538

ABSTRACT

A series of pyrrole-indolin-2-ones were synthesized, and their inhibition profile for Aurora kinases was studied. The potent compound 33 with phenylsulfonamido at the C-5 position and a carboxyethyl group at the C-3' position selectively inhibited Aurora A over Aurora B with IC50 values of 12 and 156 nM, respectively. Replacement of the carboxyl group with an amino group led to compound 47, which retained the activity for Aurora B and lost activity for Aurora A (IC50=2.19 microM). Computation modeling was used to address the different inhibition profiles of 33 and 47. Compounds 47 and 36 (the ethyl ester analogue of 33) inhibited the proliferation of HCT-116 and HT-29 cells and suppressed levels of the phosphorylated substrates of Aurora A and Aurora B in the Western blots.


Subject(s)
Antineoplastic Agents/chemical synthesis , Indoles/chemical synthesis , Protein Serine-Threonine Kinases/antagonists & inhibitors , Pyrroles/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Aurora Kinase B , Aurora Kinases , Cell Proliferation/drug effects , Drug Screening Assays, Antitumor , HCT116 Cells , HT29 Cells , HeLa Cells , Histones/metabolism , Humans , Indoles/chemistry , Indoles/pharmacology , Models, Molecular , Phosphorylation , Protein Binding , Pyrroles/chemistry , Pyrroles/pharmacology , Stereoisomerism , Structure-Activity Relationship
10.
Bioorg Med Chem Lett ; 17(22): 6373-7, 2007 Nov 15.
Article in English | MEDLINE | ID: mdl-17889528

ABSTRACT

A series of C-6 or C-3' alkynyl-substituted 4-anilinoquinazoline derivatives was prepared straightforwardly by a Sonogashira reaction of the corresponding bromo-substituted 4-anilinoquinazolines. Bioactive assay of these compounds for in vitro EGFR kinase inhibition demonstrated that the novel 6-hydroxypropynyl-4-anilinoquinazoline 5e was a very potent EGFR kinase inhibitor with an IC(50) of 14 nM.


Subject(s)
Aniline Compounds/chemical synthesis , Aniline Compounds/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , ErbB Receptors/antagonists & inhibitors , Quinazolines/chemical synthesis , Quinazolines/pharmacology , Aniline Compounds/chemistry , Antineoplastic Agents/chemistry , Computer Simulation , Drug Screening Assays, Antitumor , Inhibitory Concentration 50 , Models, Molecular , Molecular Structure , Quinazolines/chemistry , Structure-Activity Relationship
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